Histamine {2-(imidazol-4-yl)ethylamine} is a biologically-active molecule. Histamine exerts a physiological effect via multiple distinct G-protein coupled receptors. The histamine H3 receptor was first described as a presynaptic autoreceptor in the central nervous system (CNS) (Arrang, J.-M. et al., Nature 1983, 302, 832-837) controlling the synthesis and release of histamine. Evidence has emerged showing that H3 receptors are also located presynaptically as heteroreceptors on serotonergic, noradrenergic, dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acid containing) neurons. These H3 receptors have also recently been identified in peripheral tissues such as vascular smooth muscle. Consequently, there are many potential therapeutic applications for histamine H3 agonists, antagonists, and inverse agonists. (See: “The Histamine H3 Receptor-A Target for New Drugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000, 408, 860-864.)
Several indications for histamine H3 antagonists and inverse agonists have similarly been proposed based on animal pharmacology and other experiments with known histamine H3 antagonists (e.g. thioperamide). These include dementia, Alzheimer's disease (Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21, 1977), epilepsy (Yokoyama, H. et al., Eur. J. Pharmacol. 1993, 234, 129-133), narcolepsy, with or without associated cataplexy, cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence, excessive daytime sleepiness (EDS), circadian rhythm disorders, sleep/fatigue disorders, fatigue, drowsiness associated with sleep apnea, sleep impairment due to perimenopausal hormonal shifts, jet lag, Parkinson's-related fatigue, multiple sclerosis (MS)-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, eating disorders (Machidori, H. et al., Brain Res. 1992, 590, 180-186), motion sickness, vertigo, attention deficit hyperactivity disorders (ADHD), learning and memory (Barnes, J. C. et al., Soc. Neurosci. Abstr. 1993, 19, 1813), and schizophrenia (Schlicker, E. and Marr, I., Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 353, 290-294). (Also see: Stark, H. et al., Drugs Future 1996, 21 (5), 507-520; and Leurs, R. et al., Prog. Drug Res. 1995, 45, 107-165 and references cited therein.) Histamine H3 antagonists, alone or in combination with a histamine H1 antagonist, are reported to be useful for the treatment of upper airway allergic responses (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479). A more recent review of this topic was presented by Tozer and Kalindjian (Exp. Opin. Ther. Patents 2000, 10, 1045). For additional reviews, see: Celanire, S. Drug Discovery Today 2005, 10 (23/24), 1613-1627; Hancock, A. A. Biochem. Pharmacol. 2006, 71, 1103-1113.
The compounds of the present invention display potency at the human H3 receptor as determined by receptor binding to the human histamine H3 receptor (see Lovenberg, T. W. et al., Mol. Pharmacol. 1999, 55, 1101-1107). Screening using the human receptor is particularly important for the identification of new therapies for the treatment of human disease. Conventional binding assays, for example, are determined using rat synaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992, 263 (1), 304-310), rat cortical membranes (West, R. E. et al., Mol. Pharmacol. 1990, 38, 610-613), and guinea pig brain (Korte, A. et al., Biochem. Biophys. Res. Commun. 1990, 168 (3), 979-986). Only limited studies have been performed previously using human tissue or the human receptor, but these indicate significant differences in the pharmacology of rodent and primate receptors (West, R. E. et al. Eur. J. Pharmacol. 1999, 377, 233-239; Ireland, D. et al. Eur. J. Pharmacol. 2001, 433, 141-150).
To achieve a desired pharmacological effect, a compound must display potency against the biological target, as well as a suitable pharmacokinetic profile. First, the compound must be able to travel to its site of action, whether in the CNS, requiring adequate permeation of the blood-brain barrier, or in the periphery. Absorption through various biological membranes is dependent on the physical properties of the drug (degree of ionization at physiological pH, partition coefficient, molecular size, among other factors). Once the desired pharmacological effect is produced, a drug must be eliminated from the organism at a suitable rate. Where an elimination process is too slow, an accumulation of the drug can occur, potentially causing undesirable side effects.
Various H3-mediated diseases may require compounds with distinct and different pharmacokinetic profiles. In particular, administration of a compound with a short half-life provides greater control over exposure and duration of action of the drug, which may be advantageous in treating or preventing a particular disease or condition. A compound with such an optimized profile allows for the use of tailored formulations, dosing regimens, and/or delivery strategies to accomplish these results. For example, a compound with an attenuated pharmacokinetic profile may produce a shorter pharmacodynamic effect, which may be preferable in treating certain disease states. In contrast, a compound with a long half-life may be preferred for conditions in which constant occupancy of the target by the drug, with no or only very minor changes in drug concentration, are desirable.
Various piperazinyl benzamides were disclosed in U.S. Patent Appl. Publication No. US-2004-0110746-A1 (Jun. 10, 2004), which is hereby incorporated by reference.
The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety.
Described herein is a series of N-cyclopropyl amine compounds with the ability to modulate the activity of the histamine receptor, specifically the H3 receptor.